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BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3

Nature volume 425, pages 316–321 (2003)Cite this article

Abstract

Programmed destruction of regulatory proteins through the ubiquitin–proteasome system is a widely used mechanism for controlling signalling pathways1,2. Cullins3 are proteins that function as scaffolds for modular ubiquitin ligases typified by the SCF (Skp1–Cul1–F-box) complex4,5,6. The substrate selectivity of these E3 ligases is dictated by a specificity module that binds cullins. In the SCF complex, this module is composed of Skp1, which binds directly to Cul1, and a member of the F-box family of proteins4,5,6,7. F-box proteins bind Skp1 through the F-box motif7, and substrates by means of carboxy-terminal protein interaction domains1,2,5. Similarly, Cul2 and Cul5 interact with BC-box-containing specificity factors through the Skp1-like protein elongin C2. Cul3 is required for embryonic development in mammals and Caenorhabditis elegans8,9,10 but its specificity module is unknown. Here we report the identification of a large family of BTB-domain proteins as substrate-specific adaptors for C. elegans CUL-3. Biochemical studies using the BTB protein MEL-26 and its genetic target MEI-1 (refs 12, 13) indicate that BTB proteins merge the functional properties of Skp1 and F-box proteins into a single polypeptide.

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Figure 1: Interaction of C. elegans CUL-3 with BTB-domain-containing proteins.
Figure 2: Sequence requirements for interaction of BTB-domain-containing proteins with CUL-3.
Figure 3: MEL-26 associates with its genetic target, MEI-1.
Figure 4: MEL-26 interacts with the N terminus of MEI-1 through its MATH domain.

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Acknowledgements

We thank M. Peter for anti-CUL-3 and anti-MEL-26 antibodies. This work was supported by an NIH grant (to J.W.H. and S.J.E.), the Welch Foundation (to J.W.H.), and the National Human Genome Research Institute (to M.V.). Y.W. was supported by a Department of Defense predoctoral fellowship. S.J.E. is an investigator of the Howard Hughes Medical Institute.

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Author notes

  1. J. Wade Harper

    Present address: Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, 02115, USA

  2. Stephen J. Elledge

    Present address: Center for Genetics and Genomics, Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, 02115, USA

  3. Jerome Reboul

    Present address: INSERM Unite 119, Institut Paoli Calmette, 13009, Marseille, France

  4. Lai Xu and Yue Wei: These authors contributed equally to this work

Authors and Affiliations

  1. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Lai Xu, Stephen J. Elledge & J. Wade Harper

  2. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Yue Wei & J. Wade Harper

  3. Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Stephen J. Elledge

  4. Department of Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Tae-Ho Shin

  5. Dana Farber Cancer Institute, Department of Genetics, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Jerome Reboul, Philippe Vaglio & Marc Vidal

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Correspondence to J. Wade Harper.

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Xu, L., Wei, Y., Reboul, J. et al. BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature 425, 316–321 (2003). https://doi.org/10.1038/nature01985

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